The central focus of our lab is to define the mechanisms responsible for NK cell recognition, and to[unreadable] determine the role of NK cell receptors and their ligands in immunity against virus-infected cells and tumors.[unreadable] In this competitive renewal application, we propose to continue our efforts towards this goal by addressing[unreadable] three promising new areas in human and mouse NK cell biology. Specific aims are: 1) To determine how[unreadable] mouse NK cells use the activating Ly49P receptor to recognize cytomegalovirus (CMV)-infected cells and[unreadable] provide protective anti-viral immunity, 2) To define the specificities of activating human NK cell receptors for[unreadable] ligands presented by virus-infected cells and by dendritic cells, and 3) To evaluate the function of the[unreadable] human NKR-P1A receptor and its ligand. For aim 1, we have preliminary data showing that the activating[unreadable] Ly49P receptor express by NK cells in MCMV-resistant MA/My mice recognizes MCMV-infected cells, but[unreadable] only if the MCMV-infected cells express H-2k suggeting for the first time that NK cell recognition of a[unreadable] pathogen may be MHC-restricted. We outline strategies to define this mechanism of recognition in vitro and[unreadable] vivo. For aim 2, we have established a powerful new function-based expression cloning strategy, and have[unreadable] validated its use in identifying ligands on human EBV-transformed B cells that activated human NK cells.[unreadable] We will now use this strategy to elucidate how human NK cells recognize human CMV-infected cells and[unreadable] how human NK cell interact with dendritic cells. In the final aim, we have recently identified a ligand for the[unreadable] human NKR-P1A (CD161) receptor, and will conduct studies to define the function and signaling resulting[unreadable] from this receptor-ligand interaction. Collectively, this project will further our understanding of how mouse[unreadable] and human NK cells contribute to immunity againts virus-infected cells and tumors.